Insufflation apparatus and methods

ABSTRACT

An insufflation apparatus and methods for using same are disclosed. The apparatus is equipped with an interactive system for administering reproducible intratracheal aerosols in a consistent automated manner. The insufflation system is useful, in particular for use with experimental animals, including mice and rats and also for treating small animals via the pulmonary route in veterinary medicinal practice.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional patentapplication No. 61/862,484, filed Aug. 5, 2013, the entire disclosure ofwhich is incorporated herein by reference.

TECHNICAL FIELD

The present disclosure relates to a drug delivery system, including aninsufflation apparatus and methods for delivering a consistent powderdischarge to an animal's lungs during inhalation cycles. In particular,the apparatus is configured with an automated computerized system whichcan be used to deliver drugs by insufflation, for example, toexperimental animals for local and/or systemic drug administrationstudies. The apparatus achieves drug delivery with consistency andreproducibly.

All references cited in this specification, and their references, areincorporated by reference herein in their entirety where appropriate forteachings of additional or alternative details, features, and/ortechnical background.

BACKGROUND

The pulmonary route of administration is useful for delivering medicinesinto the lungs for treatment of local conditions or to achieve systemicabsorption. For local treatments, the medicine can be delivered directlyto the site of need where the compound can exert effect. Most currentdrugs delivered to the lungs are designed to have an effect on thetissue of the lungs. Examples of drugs for lung delivery include,vasodilators, surfactants, chemotherapeutic agents, or vaccines for flu,or other respiratory illnesses for the treatment of diseases, including,asthma, COPD, cystic fibrosis, and pulmonary infections. Pulmonaryadministration enables rapid treatment of these chronic and acuteconditions. Drug formulations for treating pulmonary diseases such asasthma are available by several methods, including, using nebulizerssuch as treatment with PULMOZYME®, using metered-dose inhalers such asSYMBICORT®, and dry powder inhalers such as ADVAIR DISKUS®, PULMICORTFLEXHALER®. Other types of treatments, including biologics such asnucleotides drugs in genetic therapy have been delivered to the lungs,for example, for gene therapy of cystic fibrosis, where retroviralvectors expressing an effective adenosine deaminase are administered tothe lungs.

Currently, formulations for treating systemic disease using biologicproducts are available primarily through injectable compositions. Drypowder compositions for pulmonary inhalation and systemic delivery ofinsulin have been used, including EXUBERA®, and AFREZZA®.

In cases where systemic absorption is desired, the large surface area ofthe lung, its thin wall structure, and its local proximity to thesystemic circulation are beneficial. Drug delivery to the lungs providesadvantages over oral administration of active agents such as proteinsand peptides, which are sensitive to enzymatic deactivation ordegradation in the gut. In addition, absorption through the lungs intothe systemic circulation is more effective in reaching target tissues,bypassing the liver, which is the site of metabolic action of most drugsdelivered by injections and other routes of administration. Thepotential for delivering many other compounds through the lungs forsystemic administration, ranging from peptides and proteins to smallmolecules often requires numerous studies and approaches depending onthe delivery system used.

For pulmonary delivery, medicines are often formulated into a liquid ordry powder format so that they can be aerosolized and inhaled bypatients. Aerosolization is achieved by delivery devices such asinhalers, atomizers, and nebulizers, which convert a payload of theliquid or dry powder formulation into a respirable dispersion. Thedispersion is comprised of particles suitably small for navigating theairway and depositing in the lung. Particles that are too large carryexcessive inertia, impact the back of the throat, and are swallowed.Particles that are too small can be exhaled and never deposit in thelung.

Early development work on drug formulations often requires non-clinicaltesting. This may involve small animals, including, mice, rats and otherrodents, wherein drug delivery, exposure and the resulting effects canbe studied before progressing to large animals and into humanadministration studies. Pharmacokinetic and pharmacodynamic effectsalong with adverse events can be assessed using an animal model to helpprogress or halt development of candidate drug formulations. It istherefore, extremely important in evaluating a potential drug that thedelivery of the formulation being tested is consistent to ascertain withmore accuracy the envisioned delivery in humans. For example, if thedrug is intended for delivery in a single inhalation using an inhalertogether with a dry powder formulation, then the small animal testingshould approximate the envisioned approach in humans.

Current model methodologies used to assess delivery and efficacy ofdrugs for pulmonary delivery, include liquid instillation or dry powderinsufflation. These methods have been developed by researchers to enableplacement of candidate drug formulations directly into the lung. Themethods involve syringe-like systems such as the PennCentury DP-4,wherein an elongated blunted cannula, dry powder chamber and syringe areused to disperse the contents of the chamber into the animal's lungs. Toperform the insufflation, the animal is lightly anesthetized andintubated to insert the device cannula past the vocal cords and into thetrachea just before the carina, the tracheal bifurcation leading intothe bronchi. Oftentimes, a laryngoscope is used to help the researcherguide the cannula during the insertion step. The syringe barrel is thendepressed forcing the contents, either liquid, suspension, or powder outof the chamber, down the cannula, and into the animal's lung. The airvolume to discharge the powder from an insufflator is typically between1.0 to 5.0 mL depending on the animal species. Using this equipment, avalve feature within the powder chamber prevents air flow and thesubsequent aerosolization until a minimum threshold pressure isachieved. Accordingly, researchers exert significant manual force todepress the syringe plunger during activation thereby aerosolizing thecontents of the chamber with minimal air volume.

Two major challenges are encountered with the aforementioned techniques.The first challenge is one of timing delivery of the drug during thebreathing cycle. Discharge of powder into an animal during exhalationresults in sub-optimal delivery as the contents can be blown back andare not delivered to the test subject. With powder delivery, powder blowback condition results in exhalation of drug, making it impossible toestimate the magnitude of drug delivery and confounding any measurableeffects by the drug. Manual discharge of powder or liquid to avoid blowback is difficult in animals with high respiratory rates and or smalllung capacity, for example, in mice having typically, 90 breaths perminute. The second challenge is repeatability and/or consistency.Current technology requires a minimum pressure to disperse a drugformulation. The devices allow for a range of pressures above thatminimum which affect both the quality and consistency of the dispersion.Airflows occurring with the minimum required pressure may produce anaerosol discharge with large particle sizes that are not able to beinhaled deep into the lung. Large sizes are prevented from navigatingdeep into the lung because inertial forces become too large forcing thedrug laden particles into the upper airway branches of the lung.Conversely, airflows occurring with higher applied pressures may produceaerosol discharges with far greater quality. Particle sizes within theseemitted aerosols will likely be reduced and therefore will have a muchgreater likelihood of depositing deeper in the lung. The dependence ofconsistency on the applied syringe plunger pressure is also difficult toovercome. Instillation and/or insufflation studies typically involvemultiple animals which can lead to variations in drug delivery fromanimal to animal if procedures are manually executed. Sources ofvariation in the drug delivery make assessment of drug effect moredifficult to interpret.

Dosing reproducibility during experiments requires that the drugformulation be delivered to the subject with consistent and reproducibleresults. Therefore, the inventors have seen the need to design andmanufacture an apparatus, system, and method to overcome the problemsencountered with standard apparatuses and procedures currently used.

SUMMARY

A drug delivery system is provided comprising an apparatus and a methodfor delivering a drug composition, including aerosolized particles tothe lungs are disclosed.

The apparatus comprises devices configured for measuring and recordingan animal's breathing cycles; ascertaining the intervals of thebreathing cycles and delivering an aerosol at a predetermined intervalrelative to an animal's breathing, in particular during an inhalation.The apparatus can comprise one or more sensors selecting from a varietyof sensors, including, but not limited to accelerometers, microphones,strain gauges and transducers.

In one embodiment, computer algorithms specific to the sensors can thencharacterize and quantitate the animal's breathing pattern and determinewhen to trigger the insufflation in order to synchronize delivery with anatural inhalation maneuver. In one embodiment, delivery of dosecomposition can also be synchronized with different portions of thebreathing cycle prior to or during an inhalation. The duration of theinhalation can also be checked, and assessed to determine the extent ofdelivery relative to the start and end of the inhalation. In oneembodiment, active monitoring of the animal's breathing also generatesdata on duration of inhale/exhale, regularity of breathing, and othercharacteristics of the breathing cycle. In this and other embodiments,the apparatus is provided with an automated driving mechanism thatdisplaces air through the insufflation device, by adapting anelectromechanical device. In one embodiment, a linear solenoid can beused to displace a driving pump's piston, which ensures repeatabledriving force and results in repeatable discharge flow rates.

In one embodiment, an apparatus is provided comprising:

a first device comprising a platform comprising an area for positioningan animal and configured to hold an animal in place and comprising anadjustable strap adapted with at least one sensor which detects movementof distension of the animal's thorax and/or abdomen due to breathing;said sensor generates a signal and communicates the signal to amicroprocessor for analysis; and mounting means, including a stand forsecuring to said platform;

a second device comprising a solenoid, a syringe pump and a powderreservoir; wherein said solenoid is actuated by an onboard relay outputsystem to pressurize the syringe pump; said second device furthercomprising a computer interface comprising a programmable algorithmwhich detects an animal's breathing pattern and said solenoid isactuated to pressurize the syringe pump at a predetermined intervalduring an inhalation to release a powder plume from the powderreservoir.

In one embodiment, the first device can further comprise a secondsensor, which can detect sound generated from the animal's breathingcycles. In this and other embodiments, the apparatus can also compriseone or more modules comprising a relay board for relaying an outputsignal, such as an automated on and off switch; and a data acquisitionboard. In this embodiment, a first sensor communicates a first set ofinput signals to a first microprocessor configured with a dataacquisition board which captures the input signals from the sensors,processes and analyzes the first set of signals in the first device andcontinuously streams to a computer and communicates with a relay boardto actuate the solenoid and pressurize the syringe to discharge a powdercontained in the powder reservoir at a predetermined interval.

In one embodiment, the first device comprises an adjustable cantileveredarm on which a transducer is mounted and can be positioned in thedesired position on an animal to best measure physiological changesassociated with breathing, such as diaphragm distention.

In a particular embodiment, a drug delivery system is providedcomprising: an air pump adapted with a solenoid; an insufflation orinstillation device adaptable to said air pump and comprising a chamberfor containing a drug composition and a cannula; one or more sensorswhich can detect signals from breathing cycles of an animal; and a dataacquisition board comprising an executable algorithm analyzing andtransmitting signals from said one or more sensors, wherein theexecutable algorithm contains instructions to actuate the solenoid at apredetermined interval of a breathing cycle of the animal. In an exampleembodiment, the acquisition board can process the signals from thesensors within a computer, which makes the system modular, or can bepart of a microprocessor built-in with the solenoid. In one embodiment,the animal is anesthetized and the system can have at least two sensors,including an accelerometer and a microphone.

In further embodiments, a method for insufflating an animal, includingfor example dogs, cats, monkeys, and rodents such as a mouse or a rat isdisclosed. In a particular embodiment, the method comprises:anesthesizing an animal; positioning one or more sensors on or near theanimal in the insufflation apparatus; detecting and analyzing theanimals breathing cycles and administering a dose of a test compositionat the inhalation interval of said animal. In an alternate embodiment,the method can also be used to instill a solution, a suspension, and/ora vapor to an animal.

In a particular embodiment, detecting and analyzing the animal'sbreathing cycles comprises positioning one or more sensors, such as anaccelerometer, a microphone, or a transducer on or near the animal,which sensor(s) can detect signals from the animal, and transmit thesignals to a data acquisition board, through which signals are analyzedand evaluated using an algorithm executable by, for example, amicroprocessor on board a computer, or a programmable logic controller(PLC).

In one embodiment, signals from one or multiple sensors including, butnot limited to microphones, thermocouples, strain gauges,accelerometers, and the like are used to optimally position thesensor(s) relative to the animal. In this embodiment, positioninginformation is relayed via a computer interface in which an algorithmdetects the sensor output. An algorithm determines if the position isacceptable using sensor specific criteria, for example, validity ofsignal to noise, peak detection, slope detection, baseline noise and thelike. The positioning of the sensor can occur manually by an operator orautomatically using computer controlled, including motors andpneumatics, and sensor feedback.

In one embodiment, the method comprises, positioning an animal to betested to an accessible area, for example, strapping the animal to aplatform comprising an adjustable belt comprising one or more sensor(s),including an accelerometer, a transducer and/or a microphone;positioning the one or more sensor(s) to detect one or more signalsgenerating from the animal's breathing cycles; actuating a power sourceand setting the accelerometer to detect a predetermine number of inputsignals to characterize the breathing pattern of the animal; anddelivering an aerosolized powder plume to the animal during aninhalation. In a specific embodiment, the method comprises, determiningthe animal's breathing rate and inhalation intervals; and delivering adose of an aerosolized composition at an inhalation interval. In someembodiments, the animal can optionally be strapped to the platformcomprising a restraining area. In some embodiments, the adjustable beltcan comprise an elastic material.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a schematic representation of an embodiment of the drugdelivery system or apparatus.

FIG. 2A depicts a schematic representation of the apparatus embodimentof FIG. 1, illustrating the details of a platform embodiment adaptedwith a strap containing an accelerometer for positioning on an animal.FIG. 2B depicts FIG. 2A showing a balloon mouse simulator adapted to theapparatus for in vitro testing studies.

FIG. 3 depicts a schematic representation of an embodiment devicecomponent of the apparatus of FIG. 1 showing a solenoid and syringe pumpsystem.

FIG. 4 depicts a schematic representation of an embodiment herewithdepicting a flow chart illustrating the functional systems associatedwith the apparatus of FIG. 1

FIG. 5 depicts an embodiment of the insufflation device for adapting tothe apparatus illustrated in FIG. 1 and containing a drug chamber orreservoir and showing a cannula for intubating an animal and deliveringa powder dose.

FIG. 6A is a photograph of platform section of the embodimentillustrated in FIG. 1 showing its components part and an attachedballoon simulation adaptor is showing in FIG. 6B to represent a smallanimal.

FIG. 7 is a computer screenshot showing an output signal from anembodiment apparatus which signal was obtained using a balloon connectedto a pump (FIG. 6B setup) to simulate breathing by mimicking inflate anddeflate such as during a breathing cycle for a small rodent andassembled into the device.

FIG. 8 is a schematic representation of an alternate platform embodimentof the apparatus embodiment of FIG. 1, depicting a movable cantileveredarm containing a linear positioning sensor for use with smallexperimental animals.

FIG. 9 is a schematic representation of a modified top view of theplatform embodiment in FIG. 8 showing the positioning of the cantilevermoveable on a stage.

FIG. 10 is schematic representation of the functional components of theoperating system of the drug delivery apparatus.

FIG. 11 is a schematic representation of the hardware communicationsystem of an embodiment of the herein described apparatus.

FIG. 12 is schematic representation of the insufflation sequence usingan example embodiment apparatus for use with an experimental animal.

FIG. 13 is a computer screenshot showing an output signal generated fromdata obtained from an insufflation study with an embodiment apparatus inuse during an insufflation of a Sprague Dawley rat as exemplified inFIGS. 8 and 9.

DETAILED DESCRIPTION

In embodiments disclosed herein, there is disclosed an apparatus, asystem, and a method for delivering drugs to an animal by insufflation.

In an exemplary embodiment illustrated in FIGS. 1-7, there is disclosedan insufflation apparatus with an interactive system and methods foradministering intratracheal aerosols to small animals, including miceand rats. The apparatus 10 can be used to deliver aerosols in drypowder, suspension, or in liquid form. In one embodiment, the apparatus10 can be used to insufflate, for example, mice, or Sprague-Dawley ratswith dry powder aerosols for delivering test drug formulations inresearch and development, and for use in small animal practice inveterinary medicine, including, dogs, cats, guinea pigs, hamsters,monkeys, and the like.

In this embodiment and illustrated in FIG. 1, the insufflation apparatus10 comprises a stand, a platform 14 (FIGS. 2A and 2B) for positioning ananimal, including a mouse or a rat, a movable adjustable retainer 9, adata acquisition system (not shown), a strap 13 comprising a sensor 15such as an accelerometer and/or microphone, a solenoid 17 adapted to asmall volume air pump 16 (FIG. 3), and a unit-dose reusable insufflationdevice (FIG. 5) to disperse pre-metered masses of powder from a powderreservoir adapted with a cannula 28. In this embodiment, the apparatuscomprises a sensor 18 such as microphone and an accelerometer 19 tomonitor breathing signals, including, sound signals, air flow, chest ordiaphragm distention signals, and the like. In some embodiments, theapparatus may comprise a single sensor or multiple sensors, which can beused to detect different types of signals from the animal and include,but are not limited to, transducers, strain gauges, pressure gauges, orthermistors.

FIG. 4 is a schematic representation of an embodiment herewith, andillustrates an example of the physical and/or electronic interactionsbetween various components of apparatus 10, wherein apparatus 10comprises two sensors, a first sensor which can be an accelerometer 19for detecting distension of the abdomen, and a second sensor, forexample, a miniature microphone 19 for detecting breathing soundsgenerated from the breathing cycles of an animal. In this embodiment,both types of signals generated from the first sensor 18 and secondsensor 19 are relayed to a data acquisition board 22, which receives thedifferent types of signals and streams them to a software interfacecomprising real-time breathing monitoring analysis and processingcapabilities of an animal's breathing cycles. Apparatus 10 is controlledwith software algorithms to correlate characteristic electrical signalsfrom the sensors to the animal's breathing. FIG. 4 also shows thatoutput signals from data acquisition board 22 are sent to an automatedpump controller 26 to actuate solenoid 17 adapted to syringe pump 16 toautomatically actuate the solenoid when an insufflation maneuver isneeded to administer a dose during a test or treatment procedure.

In this and other embodiments, the actuation of the air pump 16 bysolenoid 17 can also be controlled to exert constant or varying forcelevels based on selection of hardware and software algorithm features.In one embodiment, the trigger of the automated air pump 16 iscontrolled by an executable algorithm and can then be actuated at anypoint in the breathing cycle. This will allow for triggering of the pumpoffset from a feature within the breathing cycle or in a mannerpredictive of inhale, exhale, or other marker in the breathing cycle. Inthis embodiment, the optimal actuation is expected to be upon start ofan animal's inhalation period. In one embodiment, aerosol delivery willoccur in a single or multiple short bursts and during a single, ormultiple consecutive, or non-consecutive inhalations depending on thedose and the animal.

In an exemplary embodiment as disclosed in FIGS. 1 through 5, FIG. 1illustrates an animal stand 12, 14, and a solenoid 17 driven hand pump16. FIG. 2 provides a close-up of the animal stand pictured in FIG. 1comprising: platform 14, an animal retaining adjustable bar device 9 andanimal strap 13 comprising sensor 19. In this particular embodiment,animal stand 14 comprises a microphone slide 20 and bracket 21,microphone 18, hanging wire and neck support post 9, adjustable strap 13mounts and the strap with accelerometer 19 mounted to it. In thisembodiment, the rat is meant to hang from wire 9 by its incisors, andthe neck post provides support and alignment for the rear of theanimal's neck. The strap 13 and accelerometer 19 are designed to bepositioned over the diaphragm on the chest-abdomen area to detect theanimal's breathing cycles. Microphone 18 is positioned near the animal'snose, to be able to monitor its breathing cycles. Data is collected frommicrophone 18 and accelerometer 19 by analog ports on data acquisitionboard 22, and an executable algorithm is run which converts both theaccelerometer and microphone signals into information describing theanimal's breathing pattern.

FIG. 2B is the embodiment of FIG. 2A comprising an adaptor for in vitrostudies of the insufflation apparatus and comprising a balloonpositioned in the center of the adaptor and connected to an air pumpwhich inflates the balloon at predetermine intervals to simulatebreathing patterns of a small animal. In one embodiment, the air pump isautomatically controlled by a computer program.

FIG. 3 is a drawing of an embodiment, which provides a close-up or moredetailed view of the automated pump embodiment in FIG. 1. The automatedair pump assembly 16 comprises an adjustable spring return hand pump, asolenoid mounting cylinder 17 and a solenoid 24. In one embodiment, thedischarge volume of hand pump 16 can be adjusted to volumes less thanthe animal's regular or tidal breathing volume to reduceover-pressurizing the animal's lung during an insufflation procedure.For a small animal, the air pump can discharge volumes less than 5 ml,less than 3 ml, less than 2 ml, or less than 1 ml, depending on theanimal to be insufflated. In one embodiment, the volume of pressurizedair delivered by syringe pump 16 is from about 0.25 ml to about 1.5 ml,or from about 1 to 1.5 ml. In some embodiments, larger volumes greaterthan 3 ml of air can be delivered depending on the animal and the sizeof the dose to be administered. In one embodiment, the syringe pump isdriven by solenoid assembly, which generates results in a repeatablemanner and consistent force profile, since force is applied in aconsistent manner. The automated air pump assembly in use provides areduction in air volume required in typical insufflators to deliver thecontents of a dose from the insufflation device, thus limiting dosecontent blow back post insufflation.

FIG. 4 specificaly depicts a block diagram showing the sequence requiredfor automation. In this embodiment, the apparatus 10 can be activated bypushing the run button on the software interface. The actuation triggerof apparatus 10 begins the collection of signals from both theaccelerometer 19 and microphone 18. The analog signal from accelerometer19 is processed before data acquisition board 22. Analog signals fromeach sensor 18, 19 are transmitted to the data acquisition board 22,which then transmits the signals to the software in a computer or PLCfor additional processing and real time analysis. Using the software setof instructions, the signals from each sensor 18 and 19 are convertedinto signals describing the breathing pattern of the animal withrelevant parameters, for example, duration of inhale, duration ofexhale, breaths per minute, change in breathing rate, tidal volume, andthe like. The computer software 29 instructions enables the rapididentification of the start of the animal's inhalation maneuver, andthus allows for the actuation of the pump and discharge of the drugliquid, suspension or powder prior to the end of a single inhalation. Insome embodiments, if the quantity of drug exceeds a volume that can beadministered in one inhalation, it is possible to administer the drug bya predetermined number of consecutive inhalations, or at predetermineintervals that can skip one or more inhalations.

As previously stated, the insufflation system can be used to administerliquids, suspensions and dry powders by intratracheal insufflation. FIG.5 depicts an embodiment of a single dose reusable insufflation device30, which can be adapted to apparatus 10 in series with air pump 16 foruse with a small animal such as a rodent insufflation system. In thisembodiment, the insufflation device 30 can be designed to administervarious types of composition, including dry powders and comprises asubstantially cylindrical body in the form of a syringe 30. In oneembodiment, insufflation device 30 can connect to automated air pump 16by a short tube 17a. The device can be made of materials, includingmetal to alleviate static effects on the drug composition beinginsufflated. The insufflation device 30 further comprises a chamber 15with one or more valves for containing a powder composition. Inalternate embodiments, the chamber 15 can comprise a reservoir forliquids or suspensions for use in instillations. The tip of theinsufflation device 30 comprises a blunt cannula 28, which is used todirectly intubate an anesthetized animal. Once the animal is intubated,the blunt end of the cannula is for positioning through the animal'smouth until it reaches near the carina of the tracheal region of therespiratory tract to ensure lung deposition of the drug composition tobe insufflated. FIG. 5 also illustrates the insufflation device 30further comprising an air inlet port 32 for allowing air into the pumpupon retraction of the piston of the syringe pump 16; and one or morevalves (not shown) to regulate air intake and powder containment inchamber 15 prior to delivery. Moreover, chamber 15 can be remove fromthe short tube 17a with or without cannula 28 to provide replacement ofindividual dosing units.

In an alternate embodiment, the insufflation apparatus comprises aplatform 40 for use with animals that may not need to be strapped orrestrained. In this embodiment shown in FIGS. 8 and 9, platform 40 ismounted on a stand 42 comprising base 44, support beams 46, 46′ adaptedwith hinge 48 configured to hold platform 40 and a shaft 45 to hold andsupport an air pump; solenoid and insufflation device. In thisembodiment, platform 40 supported by a stand 43 configured on base 44and it is designed to comprise an adjustable stage assembly 50comprising a cantilevered arm 52 that can be moved to differentpositions depending on the size of the animal to be insufflated. In oneembodiment, arm-like structure 52 is connected to platform 40 through ajoint to pivot, rotate and or extend, and can be placed over the abdomenof the animal. FIG. 9 is a modified top view of a portion of theapparatus illustrated in FIG. 1 adapted with a platform as shown inFIGS. 8 and 9. As seen in FIGS. 8 and 9, sensor 54 comprises atransducer in particular, linear sensor pin 54, including, pin 56; wireposts 58, 58′; wire 60 for holding, for example, a rat by its incisorteeth; and screw 62 for adjusting or moving the stage to position andadjust the sensor on an animal. In this embodiment, screw 62 moves thecantilevered arm up and down on a vertical plane. In some embodiments,platform 40 can be adapted with a robotic arm comprising a plurality ofsensors, including sensor 54, microphones, thermistors, transducers, oran accelerometer.

In some embodiments, platform 40 can further include a nose cone 57 thatcan removably attach to the top end of the platform. Nose cone 57 canserve as a mount allowing tubing to be passed through in order to keepan animal anesthetized.

In an alternate embodiment, the sensor on the cantilevered arm cancomprise an accelerometer or other types of sensing device. The sensor54 can be placed at the distal end of the arm for monitoring breathingsignals from the animal. FIG. 8 depicts an embodiment with the swivelarm-like component of the insufflation apparatus. In an alternateembodiment, platform 40 comprises a robotic arm comprising anaccelerometer.

FIG. 10 is schematic representation of the functional components of oneoperating system of the drug delivery apparatus. As indicated in FIG.10, input signal 70 generated from an animal is detected by sensor 74once the program has been initiated to position the sensor 72. Thissignal is transmitted from the sensor to a data acquisition board andprocessed in a computer. If the sensor 76 is determined to have properposition, the signals are processed and as output as baseline breathingdata 78. If the sensor is not properly placed on the animal, the sensoris adjusted 79 until acceptable baseline signals are obtained. Whenbaseline breathing signals are properly detected, dosing can begin 80.Sensor output is detected 81 by on board system 82 and determines if thesignals indicate the start of inhalation. If the signals are not from aninhalation the system continues monitoring until it detects aninhalation upon which the system can trigger actuation of the solenoidto activate the air pump 84. In one embodiment, the insufflation systemcan be set for a single dose delivery 86. If multiple dosing or repeateddoses are to be administered, the system queries if it is the lasttrigger 86. If it is not the last trigger, the system will continue todetect inhalation signals until all doses are delivered and the outputdata 88 is displayed on a screen, printed, or saved in themicroprocessor or computer system.

FIG. 11 is a schematic representation of the hardware communicationsystem of an embodiment of the claimed apparatus. Sensor 90 which can bea microphone, accelerometer, thermistor, or transducer sends signals toa data acquisition board 91, which can be part of a microprocessor or acomputer module. Signals from the data acquisition board 91 areprocessed and analyzed using a processing algorithm 92, which detectspositioning of the sensor and/or dosing, and also communicates outputregarding the breathing patterns of the animal and about properpositioning of sensor and to computer 95. Processing algorithm 92 alsoanalyzes the inhalation information 94 from the animal and if aninhalation is detected, it directs the information to the dataacquisition board 96 for further action. The data acquisition boarddetermines if a trigger of an insufflation is required and if so itdirects the relay board 97 to actuate the solenoid 98 and activate theair pump to initiate an insufflation as the animal begins an inhalation.

FIG. 12 is schematic representation which summarizes the sequence ofsteps that are needed to performing an insufflation study using anexample embodiment apparatus for use with an experimental small animal,for example, a rat or a mouse.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the techniques disclosedherein elucidate representative techniques that function well in thepractice of the present disclosure. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments that are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLE 1 Monitoring and Delivering a Measured Dose of a PowderComposition

The photographs in FIGS. 6A and 6B depict an actual apparatus set upintended for use with a small animal, in this example, the apparatus wasdesigned for use with rodent such as a rat or a mouse. FIG. 6A depictsthe insufflation system prototype consisting of a plexiglass and metalstand and a platform. As shown in FIGS. 6A and 6B a portion of the standis visible, consisting of a Lucite platform attached to a mounting meanshaving supports for holding the platform. For testing purposes, theinsufflation apparatus herewith is illustrated using a balloon which wasmounted underneath the accelerometer strap to simulate the displacementmotion of the abdomen/thorax of a rat or mice during breathing. Theballoon is secured to the platform and for undergoing a simulationinsufflation procedure. The balloon has been positioned in the samelocation as the abdomen of the animal that would be in the process ofbeing insufflated. This configuration is to serve as a test which allowsto assess the signal captured by the accelerometer mounted at the centerof the strap. The balloon is connected to a pressurized air source and athree way valve and can thus be inflated and deflated periodically tomimic the breathing pattern of a small animal.

The screenshot in FIG. 7 acquired from an experiment with a balloonshows the control interface with a plot of the data collected from theaccelerometer and displayed on a screen. The signal is characterized bya baseline when the balloon is at rest. Upon rapid inflation anddeflation of the balloon, the accelerometer measures a rapid changingoscillating signal. The system is then set to actuate the solenoid inthe second device, an air pump (not shown) pressurizes the syringe pumpto discharge a powder from the powder reservoir at a predetermineinterval during a simulated inhalation.

EXAMPLE 2 Insufflation Experiments with Rats

Sprague-Dawley rats were used in these experiments. Rats wereanesthetized, intubated and monitored using the insufflation assemblyshown in FIGS. 5 and 8, using the method as described in FIGS. 12 and 5mg of dry powder compositions per kilogram of weight of rat.Administration of the dose to each rat was triggered by the systemduring natural inhalation as detected by the system. Data collected fromthese experiments show that the process for intubation and insufflationwas achievable for the delivery of doses of neutron activated ceriumdioxide (NM-212, Specific Activity=5.7 μCi of ¹⁴¹Ce/mg CeO₂) to the ratsduring inhalations in a consistent manner data not shown). Table 1illustrate data obtained from this study.

TABLE 1 Inhalation characteristics during insufflation. average animal #of inhalation inhalation Inhalations ID inhalations duration (s) cycle(s) per minute rat 25 10 0.260 1.275 47.1 rat 26 10 0.169 1.524 39.4 rat27 10 0.226 1.224 49.0 rat 28 10 0.108 0.685 87.5 rat 29 10 0.096 0.86369.5 rat 30 8 0.274 1.357 44.2 rat 31 9 0.182 1.041 57.6 rat 32 10 0.1150.682 88.0 rat 33 10 0.140 0.867 69.2 rat 34 8 0.216 0.897 66.9 rat 3510 0.156 1.255 47.8 rat 36 9 0.062 1.111 54.0 average 0.167 1.065 56.3

The data in Table 1 shows that the breathing cycles detected by theapparatus herein are greater than 0.5 seconds. Specifically, the datashows the rats breathing cycles detected indicated that the rats werebreathing at intervals between 0.68 and 1.52 seconds with inhalationslasting from about 62 to about 300 milliseconds.

FIG. 13 is a computer screenshot showing an output signal generated fromdata obtained from an insufflation study with an embodiment apparatus inuse during an insufflation of a Sprague Dawley rat describe herewith. Asseen in FIG. 13, each breathing cycle for the rat is shown from valleyto valley in a real-time plot of the data collected with a linearposition sensor as described in FIGS. 8 and 9.

The preceding disclosures are illustrative embodiments. It should beappreciated by those of skill in the art that the techniques disclosedherein elucidate representative techniques that function well in thepractice of the present disclosure. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments that are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or and consisting essentially of language.When used in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. A drug delivery system, comprising: an air pump adapted with asolenoid, a drug delivery device adapted to said air pump and comprisinga cannula and a chamber for containing a drug composition; at least onesensor for detecting breathing cycles of an anesthetized animal; a dataacquisition board comprising an executable algorithm for analyzing andtransmitting signals from said one or more sensors and determining anddisplaying an animal's breathing pattern, wherein said executablealgorithm contains instructions to actuate said solenoid at apredetermined interval of a breathing cycle of said anesthetized animal.2. The system of claim 1, including a second sensor configured to detectan animal's breathing.
 3. The system of claim 1, wherein the at leastone sensor is an accelerometer, a microphone, a thermistor, and/or atransducer.
 4. The system of any of claim 3, wherein the at least onesensor is a microphone.
 5. An apparatus, comprising: a first devicecomprising a platform comprising an animal positioning area comprisingan adjustable strap including at least one sensor which detectsdistention of the animal's abdomen, thorax, or abdomen and thorax due tobreathing, generates an input signal and communicates the input signalto a microprocessor for analysis; a second device comprising a solenoid,a syringe pump and a powder reservoir; wherein said solenoid is actuatedby an onboard relay output system to pressurize the syringe pump; andwherein said second device further comprises a computer interfacecomprising a programmable algorithm which detects, analyzes and sendsinstructions of the animal's breathing pattern and actuates saidsolenoid to pressurize the syringe pump at a predetermined intervalduring an inhalation.
 6. The apparatus of claim 5, further comprising amounting means for securing said platform.
 7. The apparatus of claim 5,wherein said first device further comprises a second sensor, which isconfigured to detect an animal's breathing.
 8. The apparatus of claim 5,wherein the at least one sensor is an accelerometer, a microphone, athermistor, and/or a transducer.
 9. The apparatus of claim 8, whereinthe at least one sensor is a microphone.
 10. An insufflation methodcomprising: positioning an animal in an insufflation apparatuscomprising an automated air pump syringe adapted with a solenoid;placing one or more sensors on or near the animal to detect breathingsignals of said animal, wherein the sensors are configured to detect andtransmit the breathing signals and communicate with a data acquisitionboard; analyzing the breathing signals from the animal's breathingcycles to determine and analyze the animal's breathing rate and cyclesin real-time using a microprocessor with an executable algorithm, andadministering a dose of a test composition at an inhalation interval byactuating the solenoid to generate a predetermined force at apredetermined interval of an inhalation of the animal's breathing cycle.11. The method of claim 10, wherein the insufflation apparatus furthercomprises an insufflation device comprising a cannula and a chamber tocontain a drug composition.
 12. The method of claim 10, wherein the oneor more sensors is an accelerometer, a microphone, a thermistor, or atransducer.
 13. The method of claim 10, wherein the one or more sensoris a microphone.
 14. The method of claim 10, wherein the animal isanesthetized.
 15. The method of claim 10, wherein actuating the solenoidis carried out from signals from a computer interface comprising aprogrammable algorithm.
 16. The method of claim 10, wherein actuatingthe solenoid generates air pressure in the air pump syringe whichdischarges the dose of the test composition.
 17. The method of claim 10,further comprising intubating the animal with the cannula from theinsufflation device.
 18. The method of claim 10, wherein placing of theone or more sensors on or near the animal is automated.
 19. The methodof claim 10, wherein the test composition comprises a dry powder. 20.The method of claim 10, wherein the test composition comprises a drug.